One of the defining characteristics of drug addiction is compulsive drug seeking when it is ineffective or detrimental for the individual to do so. Animal models investigating the neural basis of drug seeking have, until recently, focused little attention on characterizing addiction-related endophenotypes that differentially manifest across individuals. The development of treatments for addiction is dependent on understanding what changes occur in the brains of addicted vs. non-addicted individuals. The goal of the proposed project is to investigate the neural basis of individual differences in compulsive drug seeking. Along with cocaine self-administration, we will employ recently-described behavioral models that use clusters of addiction-related endophenotypes to identify individuals as addict-like or non-addict. In these models, such rats are reliably identified based on how strongly they persist in seeking cocaine under different types of conflict introduced in a battery of tests. The tests and the endophenotypes measured include: progressive ratio (willingness to expend effort), seeking in the presence of a paired aversive stimulus (resistance to negative outcomes), and seeking during a non-drug period (persistence despite known absence of drug). We will focus on differential neuronal adaptations in the prefrontal cortex (PFC). The PFC is consistently implicated in both driving and inhibiting drug seeking in humans and animals, and dysregulation of PFC function is thought to be a major factor in the development of addiction. It is not clear, however, how different regions of this heterogeneous structure (e.g., cingulate, prelimbic, infralimbic, and orbitofrontal cortices in the rat) interact to regulate drug seeking in addicted individuals. To address this issue, we will record the activity of multiple single neurons in each of these four PFC regions simultaneously in rats during both self-administration and performance of the addiction-characterizing tests described above. Rats will be tested and recorded during an early (~2 weeks) and late (~7 weeks) session in order to monitor PFC neural activity related to the onset of addiction endophenotypes. We hypothesize that PFC areas more directly involved in driving drug-seeking behavior (prelimbic and orbitofrontal) will have amplified seeking-related activity in addict-like individuals that strengthens over time. We also hypothesize that PFC regions more involved in inhibiting drug seeking behavior (infralimbic and cingulate) will display a gradual weakening of activity over time in addict-like rats. The dual nature of this plasticity: the strengthening of seeking-related circuits and weakening of inhibition-related circuits is proposed to be a key component of the compulsive drive to obtain drugs in addicts. These studies constitute a novel way to investigate the neural plasticity related to addiction and will produce valuable data addressing potential targets for addiction-specific treatments. . PUBLIC HEALTH RELEVANCE: Addiction to cocaine and other drugs of abuse is a serious public health concern. Addiction develops through changes in the neural circuitry that controls motivation and decision-making, ultimately leading to compulsive drug seeking irrespective of the consequences. The proposed experiments will investigate what changes occur in the prefrontal cortex over the development of addiction with the goal of identifying targets for treatment of this disease.